Involvement of c-Src kinase in the regulation of TGF-β1-induced apoptosis

• Published in: Oncogene Vol. 23; no. 37; pp. 6272 - 6281
• Main Authors: SEOK SOON PARK, EOM, Young-Woo, EUN HEE KIM, JI HYUN LEE, DO SIK MIN, KIM, Sungsub, KIM, Seong-Jin, KYEONG SOOK CHOI
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 19.08.2004; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Biological and medical sciences; Caspase; Cell death; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cytoplasmic membranes; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatocellular carcinoma; Hepatocytes; Hepatoma; Liver cancer; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Molecular and cellular biology; Src protein; Transforming growth factor-b1; Tumors; Enzyme; Transferases; Caspase; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Carcinogenesis; Peptidases; Regulation(control); c-Src; Kinase; C-Onc gene; Digestive diseases; Hydrolases; TGF-β1; Transforming growth factor β1; caspases; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207856

Transforming growth factor-β1 (TGF-β1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-β1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-β1-induced apoptosis. TGF-β1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-β1. In response to TGF-β1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-β1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-β1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-β1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-β1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/ or antiproliferative properties of TGF-β1.